Abstract

BACKGROUND In diabetic nephropathy (DN), oxidative stress disrupts normal metabolic processes, contributing to progressive kidney injury. Although Nfe2l1 (also known as Nrf1) is known to regulate oxidative stress and metabolism, its specific role in DN remains poorly understood. This study investigated how changes in Nrf1 expression influence DN-associated renal fibrosis. METHODS Nrf1 function was examined in multiple experimental settings, including: human DN kidney tissues; wild-type and proximal tubule-specific Nfe2l1 knockout mice subjected to high-fat diet plus STZ-induced DN; HK-2 cells exposed to high glucose and palmitic acid; and diabetic mice treated with the Nrf1 activator RUN-47. RESULTS Nrf1 expression was markedly reduced in kidney tissues from patients with DN, as well as in the renal proximal tubules of DN mice and in high glucose and palmitic acid-treated HK-2 cells. Proximal tubule-specific Nfe2l1 knockout in mice and siRNA-mediated Nfe2l1 knockdown in HK-2 cells both aggravated tubular injury and fibrosis. Transcriptomic profiling indicated that Nrf1 modulates lipid metabolism through the PPARα signaling pathway and that its suppression exacerbates mitochondrial damage and lipid metabolism disorders. Mechanistically, Nrf1 directly binds to the PPARα promoter to transcriptionally activate its expression. Pharmacological inhibition and activation experiments confirmed that Nrf1 exerts its protective effects at least in part via PPARα signaling. Conversely, Nrf1 overexpression in HK-2 cells or pharmacological activation by RUN-47 significantly attenuated tubular damage, fibrotic changes, and lipid metabolism abnormalities. Notably, these protective effects were abrogated in the absence of Nrf1. CONCLUSIONS